Update on circRNA Vaccines

As time advances and research continues, increasing RNA types are discovered and recognized. RNA can be categorized as mRNA, tRNA, rRNA, miRNAs, snRNA, siRNA, lncRNA, and circular RNA.

Circular RNA (circRNA) is an endogenous non-coding RNA with widespread distribution and multiple cellular functions. circRNA has a closed-loop structure without the 5' nor 3' poly-A tails. In comparison with linear RNA, circRNA reserved higher stability both in vitro and in vivo. Meanwhile, circRNA shows high conservation among different species.

Classification of circRNA

• Exon circRNA (ecircRNA) (Fig. 1A)
• Exon-introncircRNA (eIciRNA) (Fig. 1B)
• Intronic circRNA (ciRNA) (Fig. 1C)
• Precursor transfer RNA (pre-tRNA) spliced to form tRNAintronic circular RNA (tricRNA) (Fig. 1D)

Fig. 1 Biosynthesis of circRNA (Chen X, 2019)

Biological Functions of circRNA

• circRNA can be used as a biomarker for tumor diagnosis with specific expression and long-term stability.
• circRNA can function as a miRNA sponge and miRNA can control gene expression through direct base pairing.
• circRNAs can participate in the physiological and pathological processes of tumors.
• circRNAs can regulate RNA-binding proteins.
• circRNAs located in the nucleus can regulate transcription.
• A few circRNAs have the function of translation into proteins.E.g., circ-ZNF609, which is associated with polysomes, can be translated into proteins.

Latest Research

March 16, 2021, a research study with Prof. Wensheng Wei's team at Peking University, Circular RNA Vaccines against SARS-CoV-2 and Emerging Variants, was pre-published on the bioRxiv preprint platform. In the study, Wei et al. designed a circRNA vaccine against SARS-CoV-2 and its variants, and two doses of circRNA vaccine were injected intramuscularly with mice models. The result has revealed that LNP-delivered circRNA-RBD could effectively neutralize SARS-CoV-2 pseudovirus, and a strong T-cell immune response was generated in the spleen of mice. These observations suggest that the circRNA-RBD vaccine induces a durable humoral immune response and a strong T-cell immune response in mice models.

Fig. 2 Humoral immune responses in mice immunized with SARS-CoV-2 circRNARBD vaccines (Qu L, 2021)

January 11, 2022, Prof. Wensheng Wei's team updated their latest research results, and rhesus macaques were used as tested animals. Compared to the unvaccinated control group, vaccinated rhesus macaques exposed to viruses were tested with mild pneumonia and essentially undetectable viral RNA in the lung tissue. These results demonstrated circRNA vaccine could effectively protect rhesus macaques.

Fig. 3 circRNA vaccine-elicited immunogenicity and protection against SARS-CoV-2 infection in rhesus macaques (Qu L, 2021)

circRNARBD can be produced rapidly using the in vitro transcription technique and is highly stable in the absence of nucleotide modifications. As a result, circRNAs can potentially become novel vaccines as well as therapeutic platforms for future uses according to their special properties.

circRNA Emerging Companies and Financing

On November 29, 2021, THERORNA Inc., founded by Prof. Wensheng Wei, announced the completion of a Pre-A round of financing. Furthermore, companies that have received financing in the circRNA field since 2021 include OrnaTherapeutics, Laronde, and Shanghai CirCode Biology.

Today, the development of circRNA therapeutics still has a long way before reaching clinical uses. With the help of capital, we expect this innovative technology will soon enter clinical development and demonstrate its potential in disease treatment.